Streptococcus pneumoniae (S. pneumoniae) is a major cause of both acute bacterial pneumonia and acute purulent meningitis in humans. This organism efficiently colonizes the mucosal surface of the human nasopharynx, which colonization is the initial step in the pathogenesis of respiratory tract infection (Tuomanen et al., 1995, New Engl. J. Med. 332:1280-1284). S. pneumoniae is highly adapted to its human host since natural infection of other host species, even in the carrier state, is unusual. An important factor in the ability of this organism to establish a presence on mucosal surfaces is its effective evasion of local host defenses.
It is known that S. pneumoniae encodes a proteolytic enzyme which specifically cleaves the heavy chain of human immunoglobulin A1 (IgA1 ), the predominant class of immunoglobulin present on mucosal membranes (Kett et al., 1986, J. Immunol. 136:3631-3635; Kilian et al., 1979, Infect. Immun. 26:143-149; Male, 1979, Infect. Immun. 62:254-261). However, the gene encoding S. pneumoniae IgA1 protease has not been identified and the protein product has not been isolated or purified. IgA1 protease has been characterized in a number of bacteria including Neisseria gonorrhoreae (Pohlner et al., 1987, Nature (London) 325:458-462), Neisseria meningitides (Koomey et al., 1984, Immun. 43:101-107; Plaut et al., 1975, Science 190:1103-1105), Haemophilus influenzae (Bricker et al., 1983, Proc. Natl. Acad. Sci. USA 80:2681-2685; Poulsen et al., 1989, Infect. Immun. 57:3097-3105), Bacteroides melanogenicus (Mortensen et al., 1984, Infect. Immun. 45:550-557), and Streptococcus sanguis (Gilbert et al., 1988, Infect. Immun. 56:1961-1966; Gilbert et al., 1991, Infect. Immun. 59:7-17). Although each of these enzymes hydrolyses human IgA1, they represent several classes of enzymes having different catalytic activities (e.g., they comprise a serine protease, a thiol-activated protease and a metalloprotease) and have distinct cleavage sites within the heavy-chain hinge region of IgA1. The independent evolution of several distinct classes of enzymes with a similar biological function points to the importance of inactivation of IgA1 for the successful colonization of the mucosal surface by these pathogens.
There is a paucity of information on the nature of the IgA1 protease encoded by S. pneumoniae. A recent survey of 114 isolates of S. pneumoniae revealed that at least 94% of the isolates possessed the ability to hydrolyze human IgA1 (Lomholt et al., 1995, Infect. Immun. 63:4238-4243). Similar to the situation in S. sanguis and S. mitior, S. pneumoniae cleaves a single peptide bond between Pro.sub.227 and Thr.sub.228, in the heavy chain of both human and great ape IgA1, the only known substrates for this enzyme (Gilbert et al., 1988, supra; Qiu et al., 1996, Infect. Immun. 64:933-937). S. pneumoniae IgA1 protease exhibits marked antigenic variation, in that at least seventeen antigenic forms have been identified (Lomholt et al., 1995, supra).
Treatment of infection by S. pneumoniae generally involves administration of the antibiotic penicillin since the great majority of S. pneumoniae are fully sensitive to it. However, given the recent emergence of penicillin-resistant and mulitdrug-resistant strains of S. pneumoniae, other antibiotics such as erythromycin are also prescribed (Klugman, 1990, Clin. Microbiol. Rev. 3:171-196). The fact that strains of this organism have evolved which are resistant to antibiotic therapy accentuates the need for prevention by vaccination of S. pneumoniae-induced disease, for the identification of new antibiotic targets in S. pneumoniae, and for the development of antibiotics directed against those targets which are capable of inhibiting the growth and/or pathogenesis of S. pneumoniae in the human host.